Cathepsin K Targeting Matrix Regenerative Nanoparticles for Small Abdominal Aortic Aneurysm Repair

Bibliographic Details
Main Author:	Fox, Jonathan M.
Language:	English
Published:	Cleveland State University / OhioLINK 2017
Subjects:	Biomedical Engineering
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=csu1494333727788713

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-csu14943337277887132021-08-03T07:02:32Z Cathepsin K Targeting Matrix Regenerative Nanoparticles for Small Abdominal Aortic Aneurysm Repair Fox, Jonathan M. Biomedical Engineering Abdominal aortic aneurysms (AAAs) are characterized by the loss of elasticity in the aorta wall leading to a chronic increase in diameter and resulting in rupture. This is due to the lack of regeneration of elastic fibers and chronic proteolytic breakdown of elastic fibers within the aorta mediated by matrix metalloproteinases (MMPs), specifically MMP-2 and -9. Previous studies in our lab have shown cationic amphiphile-surface functionalized poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with doxycycline (DOX) to inhibit MMP activity and stimulate elastic matrix synthesis, effects we attributed to both low doses (< 10 mg/ml) of DOX released and independent effects of cationic amphiphile pendant groups on the NP surface. This promises application of these NPs to arrest or regress AAA growth since high oral DOX dosing inhibits new elastic matrix formation in the AAA wall and has undesirable side effects. In this study, we investigated feasibility of antibody-based active targeting of intravenously infused NPs to the AAA wall. Cathepsin K, a cysteine protease, is a biomarker for AAA and overexpressed in abdominal aortic aneurysm tissue making it an ideal target moiety. We have shown using a covalent conjugation method of modifying the surface of the NPs with a cathepsin K antibody resulted in a more robust antibody attachment which did not affect the DOX release profile. Cathepsin K expression was confirmed to be localized on the cell surface and utilizing cathepsin K Ab-conjugated NPs, we demonstrated an increased NP localization to the cathepsin K overexpressing cells in vitro and ex vivo. Importantly, the DOX-loaded NPs demonstrated pro-elastogenic and anti-proteolytic effects in aneurysmal smooth muscle cells supporting their use as regenerative therapies to arrest and regress AAA growth. Preliminary data has been collected indicating cathepsin K Ab-conjugated NP targeting to AAAs in elastase-injured rat models. The study outcomes support the feasibility of using cathepsin K Ab-conjugated NPs as a targeted therapy for elastic matrix regeneration in AAA tissue and will serve as a basis for already initiated follow up studies to assess NP biodistribution, in situ retention in the AAA wall, and safety as a function of time. 2017-05-23 English text Cleveland State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=csu1494333727788713 http://rave.ohiolink.edu/etdc/view?acc_num=csu1494333727788713 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center.
collection	NDLTD
language	English
sources	NDLTD
topic	Biomedical Engineering
spellingShingle	Biomedical Engineering Fox, Jonathan M. Cathepsin K Targeting Matrix Regenerative Nanoparticles for Small Abdominal Aortic Aneurysm Repair
author	Fox, Jonathan M.
author_facet	Fox, Jonathan M.
author_sort	Fox, Jonathan M.
title	Cathepsin K Targeting Matrix Regenerative Nanoparticles for Small Abdominal Aortic Aneurysm Repair
title_short	Cathepsin K Targeting Matrix Regenerative Nanoparticles for Small Abdominal Aortic Aneurysm Repair
title_full	Cathepsin K Targeting Matrix Regenerative Nanoparticles for Small Abdominal Aortic Aneurysm Repair
title_fullStr	Cathepsin K Targeting Matrix Regenerative Nanoparticles for Small Abdominal Aortic Aneurysm Repair
title_full_unstemmed	Cathepsin K Targeting Matrix Regenerative Nanoparticles for Small Abdominal Aortic Aneurysm Repair
title_sort	cathepsin k targeting matrix regenerative nanoparticles for small abdominal aortic aneurysm repair
publisher	Cleveland State University / OhioLINK
publishDate	2017
url	http://rave.ohiolink.edu/etdc/view?acc_num=csu1494333727788713
work_keys_str_mv	AT foxjonathanm cathepsinktargetingmatrixregenerativenanoparticlesforsmallabdominalaorticaneurysmrepair
_version_	1719452373643952128

Cathepsin K Targeting Matrix Regenerative Nanoparticles for Small Abdominal Aortic Aneurysm Repair

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